Peripheral amyloid-ß clearance mediates cognitive impairment in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a prevalent risk factor for cognitive impairment. Cerebral amyloid-ß (Aß) accumulation, as an important pathology of cognitive impairment, can be caused by impaired Aß clearance in the periphery. The liver is the primary organ for peripheral Aß clearance, but the role of peripheral Aß clearance in NAFLD-induced cognitive impairment remains unclear. METHODS: We examined correlations between NAFLD severity, Aß accumulation, and cognitive performance in female Sprague-Dawley rats. The impact of NAFLD on hepatic Aß clearance and the involvement of low-density lipoprotein receptor-related protein 1 (LRP-1) were assessed in rat livers and cultured hepatocytes. Additionally, a case-control study, including 549 NAFLD cases and 549 controls (782 males, 316 females), investigated the interaction between NAFLD and LRP-1 rs1799986 polymorphism on plasma Aß levels. FINDINGS: The severity of hepatic steatosis and dysfunction closely correlated with plasma and cerebral Aß accumulations and cognitive deficits in rats. The rats with NAFLD manifested diminished levels of LRP-1 and Aß in liver tissue, with these reductions inversely proportional to plasma and cerebral Aß concentrations and cognitive performance. In vitro, exposure of HepG2 cells to palmitic acid inhibited LRP-1 expression and Aß uptake, which was subsequently reversed by a peroxisome proliferator-activated receptor α (PPARα) agonist. The case-control study revealed NAFLD to be associated with an increment of 8.24% and 10.51% in plasma Aß40 and Aß42 levels, respectively (both P < 0.0001). Moreover, the positive associations between NAFLD and plasma Aß40 and Aß42 levels were modified by the LRP-1 rs1799986 polymorphism (P for interaction = 0.0017 and 0.0015, respectively). INTERPRETATION: LRP-1 mediates the adverse effect of NAFLD on peripheral Aß clearance, thereby contributing to cerebral Aß accumulation and cognitive impairment in NAFLD. FUNDING: Major International (Regional) Joint Research Project, National Key Research and Development Program of China, National Natural Science Foundation of China, and the Angel Nutrition Research Fund.

Dietary Macronutrient Intake and Cardiovascular Disease Risk and Mortality: A Systematic Review and Dose-Response Meta-Analysis of Prospective Cohort Studies.

Many epidemiological studies have evaluated the intake of macronutrients and the risk of mortality and cardiovascular disease (CVD). However, current evidence is conflicting and warrants further investigation. Therefore, we carried out an umbrella review to examine and quantify the potential dose-response association of dietary macronutrient intake with CVD morbidity and mortality. Prospective cohort studies from PubMed, Embase, and CENTRAL were reviewed, which reported associations of macronutrients (protein, fat, and carbohydrate) with all-cause, CVD, cancer mortality, or CVD events. Multivariable relative risks (RR) were pooled, and heterogeneity was assessed. The results of 124 prospective cohort studies were included in the systematic review and 101 in the meta-analysis. During the follow-up period from 2.2 to 30 years, 506,086 deaths and 79,585 CVD events occurred among 5,107,821 participants. High total protein intake was associated with low CVD morbidity (RR 0.88, 95% confidence interval 0.82-0.94), while high total carbohydrate intake was associated with high CVD morbidity (1.08, 1.02-1.13). For fats, a high intake of total fat was associated with a decreased all-cause mortality risk (0.92, 0.85-0.99). Saturated fatty acid intake was only associated with cancer mortality (1.10, 1.06-1.14); Both monounsaturated fatty acid (MUFA) and polyunsaturated fatty acids (PUFA) intake was associated with all-cause mortality (MUFA: 0.92, 0.86-0.98; PUFA: 0.91, 0.86-0.96). This meta-analysis supports that protein intake is associated with a decreased risk of CVD morbidity, while carbohydrate intake is associated with an increased risk of CVD morbidity. High total fat intake is associated with a low risk of all-cause mortality, and this effect was different in an analysis stratified by the type of fat.

Association of plasma advanced glycation end-products and their soluble receptor with type 2 diabetes among Chinese adults.

AIMS: Population-based evidence regarding circulating advanced glycation end-products (AGEs) and the risk of type 2 diabetes (T2D) is conflicting and insufficient. We aimed to examine the association of plasma AGEs and plasma soluble receptors for AGEs (sRAGE) with T2D. MATERIALS AND METHODS: We conducted a hospital-based case-control study including 1072 pairs (53.9 ± 9.7 years, 56.0% male) of newly diagnosed T2D and age- and sex-matched controls. We further performed a nested case-control study within an ongoing prospective cohort consisting of 127 incident T2D cases and 381 well-matched controls (62.2 ± 5.1 years, 71.7% male). Plasma AGEs were detected using liquid chromatography-tandem mass spectrometry, and plasma sRAGE was measured by enzyme-linked immunosorbent assay. Conditional logistic regression was used to evaluate the association of plasma AGEs and sRAGE concentrations with T2D. RESULTS: Higher plasma AGEs and lower sRAGE concentrations were associated with higher odds of T2D. The multivariable-adjusted odds ratios of T2D comparing the highest with the lowest quartile levels were 3.28 (95% CI: 2.14, 5.02) for plasma AGEs and 0.25 (95% CI: 0.16, 0.39) for plasma sRAGE. Participants in the highest quartile of plasma AGEs and the lowest quartile of sRAGE concentrations had the greatest odds of T2D. The positive association of AGEs and inverse association of sRAGE with T2D risk was confirmed in the replication-nested case-control study. CONCLUSIONS: Increased circulating AGEs and decreased sRAGE concentrations were associated with elevated T2D risk. Our findings may have implications for the strategies of T2D prevention and management.

Effects of Timing and Types of Protein Supplementation on Improving Muscle Mass, Strength, and Physical Performance in Adults Undergoing Resistance Training: A Network Meta-Analysis.

Precise protein supplementation strategies for muscle improvement are still lacking. The timing or type of protein supplementation has been debated as a window of opportunity to improve muscle mass, strength, and physical performance. We conducted a network meta-analysis of randomized controlled trials with protein supplements and resistance training. PubMed, Web of Science, Cochrane Library, and SPORTDiscus databases were searched until May 1, 2023. We included 116 eligible trials with 4,711 participants that reported on 11 timing and 14 types of protein supplementation. Compared with placebo, protein supplementation after exercise (mean difference [MD]: 0.54 kg [95% confidence intervals 0.10, 0.99] for fat-free mass, MD: 0.34 kg [95% confidence intervals 0.10, 0.58] for skeletal muscle mass) and at night (MD: 2.85 kg [0.49, 5.22] for handgrip strength, MD: 12.12 kg [3.26, 20.99] for leg press strength) was most effective in improving muscle mass and strength, respectively (moderate certainty). Milk proteins (milk, whey protein, yogurt, casein, and bovine colostrum), red meat, and mixed protein were effective for gains in both muscle mass and strength (moderate certainty). No timing or type of protein showed a significant enhancement in physical performance (timed up-to-go test, 6-min walk test, and gait speed). Pre/postexercise and Night are key recommended times of protein intake to increase muscle mass and strength, respectively. Milk proteins are the preferred types of protein supplements for improving muscle mass and strength. Future randomized controlled trials that directly compare the effects of protein timing or types are needed. This trial was registered at International Prospective Register of Systematic Reviews as CRD42022358766.

Associations of Various Physical Activities with Mortality and Life Expectancy are Mediated by Telomere Length.

OBJECTIVES: Physical activity (PA) and telomeres both contribute to healthy aging and longevity. To investigate the optimal dosage of various PA for longevity and the role of telomere length in PA and mortality. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: A total of 333,865 adults (mean age of 56 years) from the UK Biobank were analyzed. METHODS: Walking, moderate PA (MPA), and vigorous PA (VPA) were self-reported via questionnaire, and leukocyte telomere length (LTL) was measured. Cox proportional hazards regression was used to predict all-cause mortality risk. A flexible parametric Royston-Parmar survival model was used to estimate life expectancy. RESULTS: During a median follow-up of 13.8 years, 19,789 deaths were recorded. Compared with the no-walking group, 90 to 720 minutes/week of walking was similarly associated with 27% to 31% of lower mortality and about 6 years of additional life expectancy. We observed nearly major benefits for mortality and life expectancy among those meeting the PA guidelines [151-300 minutes/wk for MPA: hazard ratio (HR) 0.80, 95% CI 0.75-0.85, 3.40-3.42 additional life years; 76-150 minutes/wk for VPA: HR 0.78, 95% CI 0.75-0.82, 2.61 years (2.33-2.89)] vs the no-PA group. Similar benefits were also observed at 76-150 and 301-375 minutes/wk of MPA (18%-19% lower mortality, 3.20-3.42 gained years) or 151-300 minutes/wk of VPA (20%-26% lower mortality, 2.41-2.61 gained years). The associations between MPA, VPA, and mortality risk were slightly mediated by LTL (≈1% mediation proportion, both P < .001). CONCLUSIONS AND IMPLICATIONS: Our study suggests a more flexible range of PA than the current PA guidelines, which could gain similar benefits and is easier to achieve: 90 to 720 minutes/wk of walking, 75 to 375 minutes/wk of MPA, and 75 to 300 minutes/wk of VPA. Telomeres might be a potential mechanism by which PA promotes longevity.

Deoxynivalenol Exposure Induced Colon Damage in Mice Independent of the Gut Microbiota.

SCOPE: To investigate whether deoxynivalenol (DON) can induce intestinal damage through gut microbiota in mice. METHODS AND RESULTS: Mice are orally administered DON (1 mg kg-1 bw day-1 ) for 4 weeks, and then recipient mice receive fecal microbiota transplantation (FMT) from DON-exposed mice after antibiotic treatment. Furthermore, the mice are orally treated with DON (1 mg kg-1 bw day-1 ) for 4 weeks after antibiotic treatment. Histological damage, disruption of tight junction protein expression, and increased oxidative stress and apoptosis in the colon as well as higher serum lipopolysaccharides are observed after DON exposure. Moreover, DON exposure changes the composition and diversity of the gut microbiota as well as the contents of fecal metabolites (mainly bile acids). Differential metabolic pathways may be related to mitochondrial metabolism, apoptosis, and inflammation following DON exposure. However, only a decrease in mRNA levels of occludin and claudin-3 is observed in the colon of recipient mice after FMT. After depleting the gut microbiota in mice, DON exposure can also cause histological damage, disorders of tight junction protein expression, and increased oxidative stress and apoptosis in the colon. CONCLUSIONS: DON exposure can induce colon damage in mice independent of the gut microbiota.

The role of peripheral ß-amyloid in insulin resistance, insulin secretion, and prediabetes: in vitro and population-based studies.

Background: Previous experimental studies have shown that mice overexpressing amyloid precursor protein, in which ß-amyloid (Aß) is overproduced, exhibit peripheral insulin resistance, pancreatic impairment, and hyperglycemia. We aimed to explore the effects of Aß on insulin action and insulin secretion in vitro and the association of plasma Aß with prediabetes in human. Methods: We examined the effects of Aß40 and Aß42 on insulin-inhibited glucose production in HepG2 cells, insulin-promoted glucose uptake in C2C12 myotubes, and insulin secretion in INS-1 cells. Furthermore, we conducted a case-control study (N = 1142) and a nested case-control study (N = 300) within the prospective Tongji-Ezhou cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) for prediabetes were estimated by using conditional logistic regression analyses. Results: In the in vitro studies, Aß40 and Aß42 dose-dependently attenuated insulin-inhibited glucose production in HepG2 cells, insulin-promoted glucose uptake in C2C12 myotubes, and basal and glucose-stimulated insulin secretion in INS-1 cells. In the case-control study, plasma Aß40 (adjusted OR: 2.00; 95% CI: 1.34, 3.01) and Aß42 (adjusted OR: 1.94; 95% CI: 1.33, 2.83) were positively associated with prediabetes risk when comparing the extreme quartiles. In the nested case-control study, compared to the lowest quartile, the highest quartile of plasma Aß40 and Aß42 were associated with 3.51-fold (95% CI: 1.61, 7.62) and 2.75-fold (95% CI: 1.21, 6.22) greater odds of prediabetes, respectively. Conclusion: Elevated plasma Aß40 and Aß42 levels were associated with increased risk of prediabetes in human subjects, which may be through impairing insulin sensitivity in hepatocytes and myotubes and insulin secretion in pancreatic ß-cells.

Human milk extracellular vesicles enhance muscle growth and physical performance of immature mice associating with Akt/mTOR/p70s6k signaling pathway.

Extracellular vesicles (EVs) play an important role in human and bovine milk composition. According to excellent published studies, it also exerts various functions in the gut, bone, or immune system. However, the effects of milk-derived EVs on skeletal muscle growth and performance have yet to be fully explored. Firstly, the current study examined the amino acids profile in human milk EVs (HME) and bovine milk EVs (BME) using targeted metabolomics. Secondly, HME and BME were injected in the quadriceps of mice for four weeks (1 time/3 days). Then, related muscle performance, muscle growth markers/pathways, and amino acids profile were detected or measured by grip strength analysis, rotarod performance testing, Jenner-Giemsa/H&E staining, Western blotting, and targeted metabolomics, respectively. Finally, HME and BME were co-cultured with C2C12 cells to detect the above-related indexes and further testify relative phenomena. Our findings mainly demonstrated that HME and BME significantly increase the diameter of C2C12 myotubes. HME treatment demonstrates higher exercise performance and muscle fiber densities than BME treatment. Besides, after KEGG and correlation analyses with biological function after HME and BME treatment, results showed L-Ornithine acts as a "notable marker" after HME treatment to affect mouse skeletal muscle growth or functions. Otherwise, L-Ornithine also significantly positively correlates with the activation of the AKT/mTOR pathway and myogenic regulatory factors (MRFs) and can also be observed in muscle and C2C12 cells after HME treatment. Overall, our study not only provides a novel result for the amino acid composition of HME and BME, but the current study also indicates the advantage of human milk on skeletal muscle growth and performance.

Effect of synbiotic supplementation on immune parameters and gut microbiota in healthy adults: a double-blind randomized controlled trial.

Synbiotics are increasingly used by the general population to boost immunity. However, there is limited evidence concerning the immunomodulatory effects of synbiotics in healthy individuals. Therefore, we conducted a double-blind, randomized, placebo-controlled study in 106 healthy adults. Participants were randomly assigned to receive either synbiotics (containing Bifidobacterium lactis HN019 1.5 × 108 CFU/d, Lactobacillus rhamnosus HN001 7.5 × 107 CFU/d, and fructooligosaccharide 500 mg/d) or placebo for 8 weeks. Immune parameters and gut microbiota composition were measured at baseline, mid, and end of the study. Compared to the placebo group, participants receiving synbiotic supplementation exhibited greater reductions in plasma C-reactive protein (P = 0.088) and interferon-gamma (P = 0.008), along with larger increases in plasma interleukin (IL)-10 (P = 0.008) and stool secretory IgA (sIgA) (P = 0.014). Additionally, synbiotic supplementation led to an enrichment of beneficial bacteria (Clostridium_sensu_stricto_1, Lactobacillus, Bifidobacterium, and Collinsella) and several functional pathways related to amino acids and short-chain fatty acids biosynthesis, whereas reduced potential pro-inflammatory Parabacteroides compared to baseline. Importantly, alternations in anti-inflammatory markers (IL-10 and sIgA) were significantly correlated with microbial variations triggered by synbiotic supplementation. Stratification of participants into two enterotypes based on pre-treatment Prevotella-to-Bacteroides (P/B) ratio revealed a more favorable effect of synbiotic supplements in individuals with a higher P/B ratio. In conclusion, this study suggested the beneficial effects of synbiotic supplementation on immune parameters, which were correlated with synbiotics-induced microbial changes and modified by microbial enterotypes. These findings provided direct evidence supporting the personalized supplementation of synbiotics for immunomodulation.

Faecal microbiota transplantation from young rats attenuates age-related sarcopenia revealed by multiomics analysis.

BACKGROUND: Gut microbiota plays a key role in the development of sarcopenia via the 'gut-muscle' axis, and probiotics-based therapy might be a strategy for sarcopenia. Fecal microbiota transplantation from young donors (yFMT) has attracted much attention because of its probiotic function. However, whether or not yFMT is effective for sarcopenia in old recipients is largely unknown. Thus, we aimed to investigate the effect and mechanism of yFMT on age-related sarcopenia. METHODS: The fecal microbiota of either young (12 weeks) or old (88 weeks) donor rats was transplanted into aged recipient rats for 8 weeks. Then, muscle mass, muscle strength, muscle function, muscle atrophy, and muscle regeneration capacity were measured. Analysis of fecal 16 s rRNA, serum non-targeted metabolomic, gut barrier integrity, and muscle transcriptome was conducted to elucidate the interaction between gut microbiota and skeletal muscles. RESULTS: As evaluated by magnetic resonance imaging examination, grip strength test (P < 0.01), rotarod test (P < 0.05), and exhaustive running test (P < 0.05), we found that yFMT mitigated muscle mass loss, muscle strength weakness, and muscle function impairment in aged rats. yFMT also countered age-related atrophy and poor regeneration capacity in fast- and slow-switch muscles, which were manifested by the decrease in slow-switch myofibres (both P < 0.01) and muscle interstitial fibrosis (both P < 0.05) and the increase in the cross-section area of myofibres (both P < 0.001), fast-switch myofibres (both P < 0.01), and muscle satellite cells (both P < 0.001). In addition, yFMT ameliorated age-related dysbiosis of gut microbiota and metabolites by promoting the production of beneficial bacteria and metabolites-Akkermansia, Lactococcus, Lactobacillus, γ-glutamyltyrosine, 3R-hydroxy-butanoic acid, and methoxyacetic acid and inhibiting the production of deleterious bacteria and metabolites-Family_XIII_AD3011_group, Collinsella, indoxyl sulfate, indole-3-carboxilic acid-O-sulphate, and trimethylamine N-oxide. Also, yFMT prevented age-related destruction of gut barrier integrity by increasing the density of goblet cells (P < 0.0001) and the expression levels of mucin-2 (P < 0.0001) and tight junctional proteins (all P < 0.05). Meanwhile, yFMT attenuated age-related impairment of mitochondrial biogenesis and function in fast- and slow-switch muscles. Correlation analysis revealed that yFMT-induced alterations of gut microbiota and metabolites might be closely related to mitochondria-related genes and sarcopenia-related phenotypes. CONCLUSIONS: yFMT could reshape the dysbiosis of gut microbiota and metabolites, maintain gut barrier integrity, and improve muscle mitochondrial dysfunction, eventually alleviating sarcopenia in aged rats. yFMT might be a new therapeutic strategy for age-related sarcopenia.

Bone Marrow Mesenchymal Stem-Cell-Derived Exosomes Ameliorate Deoxynivalenol-Induced Mice Liver Damage.

Deoxynivalenol (DON) is a kind of Fusarium toxin that can cause a variety of toxic effects. DON is mainly metabolized and detoxified by the liver. When the concentration of DON exceeds the metabolic capacity of the liver, it will trigger acute or chronic damage to the liver tissue. Previous studies demonstrated that bone marrow mesenchymal stem-cell-secreted exosomes (BMSC-exos) reduce liver injury. Therefore, we issue a hypothesis that in vitro-cultured rat BMSC-secreted exos could ameliorate liver damage after 2 mg/kg bw/day of DON exposure. In total, 144 lipids were identified in BMEC-exos, including high polyunsaturated fatty acid (PUFA) levels. BMSC-exos treatment alleviated liver pathological changes and decreased levels of alanine aminotransferase, aspartate aminotransferase, inflammatory factors interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and lipid peroxidation. Otherwise, low or high BMSC-exos treatment obviously changes DON-induced hepatic oxylipin patterns. According to the results from our correlation network analysis, Pearson correlation coefficient analysis, and hierarchical clustering analysis, the top 10% oxidized lipids can be classified into two categories: one that was positively correlated with copper-zinc superoxide dismutase (Cu/Zn SOD) and another that was positively correlated with liver injury indicators. Altogether, BMSC-exos administration maintained normal liver function and reduced oxidative damage in liver tissue. Moreover, it could also significantly change the oxylipin profiles under DON conditions.

Physical frailty, adherence to ideal cardiovascular health and risk of cardiovascular disease: a prospective cohort study.

BACKGROUND: longitudinal evidence concerning frailty phenotype and the risk of cardiovascular disease (CVD) remained insufficient, and whether CVD preventive strategies exert low CVD risk on frail adults is unclear. OBJECTIVES: we aimed to prospectively evaluate the association of frailty phenotype, adherence to ideal cardiovascular health (CVH) and their joint associations with the risk of CVD. METHODS: a total of 314,093 participants from the UK Biobank were included. Frailty phenotype was assessed according to the five criteria of Fried et al.: weight loss, exhaustion, low physical activity, slow gait speed and low grip strength. CVH included four core health behaviours (smoking, physical activity and diet) and three health factors (weight, cholesterol, blood pressure and glycaemic control). The outcome of interest was incident CVD, including coronary heart disease, heart failure and stroke. RESULTS: compared with the non-frail people whose incident rate of overall CVD was 6.54 per 1,000 person-years, the absolute rate difference per 1,000 person-years was 1.67 (95% confidence interval, CI: 1.33, 2.02) for pre-frail and 5.00 (95% CI: 4.03, 5.97) for frail. The ideal CVH was significantly associated with a lower risk of all CVD outcomes. For the joint association of frailty and CVH level with incident CVD, the highest risk was observed among frailty accompanied by poor CVH with an HR of 2.92 (95% CI: 2.68, 3.18). CONCLUSIONS: our findings indicate that physical frailty is associated with CVD incidence. Improving CVH was significantly associated with a considerable decrease in CVD risk, and such cardiovascular benefits remain for the frailty population.

Healthy lifestyle behaviors, mediating biomarkers, and risk of microvascular complications among individuals with type 2 diabetes: A cohort study.

BACKGROUND: The influence of overall lifestyle behaviors on diabetic microvascular complications remains unknown. In addition, the potential mediating biomarkers underlying the association is unclear. This study aimed to examine the associations of the combined lifestyle factors with risks of total and individual microvascular complications among patients with type 2 diabetes (T2D) and to explore the potential mediation effects of metabolic biomarkers. METHODS AND FINDINGS: This retrospective cohort study included 15,104 patients with T2D free of macro- and microvascular complications at baseline (2006 to 2010) from the UK Biobank. Healthy lifestyle behaviors included noncurrent smoking, recommended waist circumference, regular physical activity, healthy diet, and moderate alcohol drinking. Outcomes were ascertained using electronic health records. Over a median of 8.1 years of follow-up, 1,296 cases of the composite microvascular complications occurred, including 558 diabetic retinopathy, 625 diabetic kidney disease, and 315 diabetic neuropathy, with some patients having 2 or 3 microvascular complications simultaneously. After multivariable adjustment for sociodemographic characteristics, history of hypertension, glycemic control, and medication histories, the hazard ratios (95% confidence intervals (CIs)) for the participants adhering 4 to 5 low-risk lifestyle behaviors versus 0 to 1 were 0.65 (0.46, 0.91) for diabetic retinopathy, 0.43 (0.30, 0.61) for diabetic kidney disease, 0.46 (0.29, 0.74) for diabetic neuropathy, and 0.54 (0.43, 0.68) for the composite outcome (all Ps-trend ≤0.01). Further, the population-attributable fraction (95% CIs) of diabetic microvascular complications for poor adherence to the overall healthy lifestyle (<4 low-risk factors) ranged from 25.3% (10.0%, 39.4%) to 39.0% (17.7%, 56.8%). In addition, albumin, HDL-C, triglycerides, apolipoprotein A, C-reactive protein, and HbA1c collectively explained 23.20% (12.70%, 38.50%) of the associations between overall lifestyle behaviors and total diabetic microvascular complications. The key limitation of the current analysis was the potential underreporting of microvascular complications because the cases were identified via electronic health records. CONCLUSIONS: Adherence to overall healthy lifestyle behaviors was associated with a significantly lower risk of microvascular complications in patients with T2D, and the favorable associations were partially mediated through improving biomarkers of glycemic control, systemic inflammation, liver function, and lipid profile.

The circadian rhythm gene Bmal1 ameliorates acute deoxynivalenol-induced liver damage.

Deoxynivalenol (DON) is widely emerging in various grain crops, milk, and wine products, which can trigger different toxic effects on humans and animals by inhalation or ingestion. It also imposes a considerable financial loss on the agriculture and food industry each year. Previous studies have reported acute and chronic toxicity of DON in liver, and liver is not only the main detoxification organ for DON but also the circadian clock oscillator directly or indirectly regulates critical physiologically hepatic functions under different physiological and pathological conditions. However, researches on the association of circadian rhythm in DON-induced liver damage are limited. In the present study, mice were divided into four groups (CON, DON, Bmal1OE, and Bmal1OE + DON) and AAV8 was used to activate (Bmal1) expression in liver. Then mice were gavaged with 5 mg/kg bw/day DON or saline at different time points (ZT24 = 0, 4, 8, 12, 16, and 20 h) in 1 day and were sacrificed 30 min after oral gavage. The inflammatory cytokines, signal transducers, and activators of transcription Janus kinase/signal transducers and activator of transcription 3 (JAKs/STAT3) pathway and bile acids levels were detected by enzyme-linked immunosorbent assay (ELISA), western blotting, and target metabolomics, respectively. The DON group showed significantly elevated interleukin-1ß (IL-1ß), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) levels (P < 0.05 for both) and impaired liver function with rhythm disturbances compared to the CON and Bmal1OE groups. At the molecular level, expressions of some circadian clock proteins were significantly downregulated (P < 0.05 for both) and JAKs/STAT3 pathway was activated during DON exposure, accompanied by indicated circadian rhythm disturbance and inflammatory damage. Importantly, Bmal1 overexpression attenuated DON-induced liver damage, while related hepatic bile acids such as cholic acid (CA) showed a decreasing trend in the DON group compared with the CON group. Our study demonstrates a novel finding that Bmal1 plays a critical role in attenuating liver damage by inhibiting inflammatory levels and maintaining bile acids levels under the DON condition. Therefore, Bmal1 may also be a potential molecular target for reducing the hepatotoxic effects of DON in future studies.

Association of Combined Healthy Lifestyles With Cardiovascular Disease and Mortality of Patients With Diabetes: An International Multicohort Study.

OBJECTIVE: To prospectively examine the associations of combined lifestyle factors with incident cardiovascular disease (CVD) and mortality in patients with diabetes. PATIENTS AND METHODS: Patients with prevalent diabetes were included from 5 prospective, population-based cohorts in China (Dongfeng-Tongji cohort and Kailuan study), the United Kingdom (UK Biobank study), and the United States (National Health and Nutrition Examination Survey and National Institutes of Health-AARP Diet and Health Study). Healthy lifestyle scores were constructed according to non-current smoking, low to moderate alcohol drinking, regular physical activity, healthy diet, and optimal body weight; the healthy level of each lifestyle factor was assigned 1 point, or 0 for otherwise, and the range of the score was 0 to 5. Cox proportional hazards models were used to estimate hazard ratios for incident CVD, CVD mortality, and all-cause mortality adjusting for sociodemographic, medical, and diabetes-related factors, and outcomes were obtained by linkage to medical records and death registries. Data were collected from October 18, 1988, to September 30, 2020. RESULTS: A total of 6945 incident CVD cases were documented in 41,350 participants without CVD at baseline from the 2 Chinese cohorts and the UK Biobank during 389,330 person-years of follow-up, and 40,353 deaths were documented in 101,219 participants from all 5 cohorts during 1,238,391 person-years of follow-up. Adjusted hazard ratios (95% CIs) comparing patients with 4 or 5 vs 0 or 1 healthy lifestyle factors were 0.67 (0.60 to 0.74) for incident CVD, 0.58 (0.50 to 0.68) for CVD mortality, and 0.60 (0.53 to 0.68) for all-cause mortality. Findings remained consistent across different cohorts, subgroups, and sensitivity analyses. CONCLUSION: The international analyses document that adherence to multicomponent healthy lifestyles is associated with lower risk of CVD and premature death of patients with diabetes.

Healthy lifestyle, plasma metabolites, and risk of cardiovascular disease among individuals with diabetes.

BACKGROUND AND AIMS: Lifestyle management is a fundamental aspect of diabetes care to prevent cardiovascular disease (CVD); however, the underlying metabolic mechanism is not well established. We aimed to identify metabolites associated with different lifestyle factors, and estimate their mediating roles between lifestyle and CVD risk among people with diabetes. METHODS: Lifestyle and metabolomic data were available for 5072 participants with diabetes who were free of CVD at baseline in the UK Biobank. The healthy level of 5 lifestyle factors was defined as non-central obesity, non-current smoking, moderate alcohol intake, physically active, and healthy diet. A total of 44 biomarkers across 7 metabolic pathways including lipoprotein particles, fatty acids, amino acids, fluid balance, inflammation, ketone bodies, and glycolysis were quantified by nuclear magnetic resonance (NMR) spectroscopy. RESULTS: All 44 assayed metabolites were significantly associated with at least one lifestyle factor. Approximately half of metabolites, which were mostly lipoprotein particles and fatty acids, showed a mediating effect between at least one lifestyle factor and CVD risk. NMR metabolites jointly mediated 43.4%, 30.0%, 16.8%, 43.4%, and 65.5% of the association of non-central obesity, non-current smoking, moderate alcohol intake, physically active, and healthy diet with lower CVD risk, respectively. In general, though metabolites that significantly associated with lifestyle were mostly different across the 5 lifestyle factors, the pattern of association was consistent between fatty acids and all 5 lifestyle factors. Further, fatty acids showed significant mediating effects in the association between all 5 lifestyle factors and CVD risk with mediation proportion ranging from 12.2% to 26.8%. CONCLUSIONS: There were large-scale differences in circulating NMR metabolites between individuals with diabetes who adhered to a healthy lifestyle and those did not. Differences in metabolites, especial fatty acids, could partially explain the association between adherence to multiple healthy lifestyle and lower CVD risk among people with diabetes.

Current studies and potential future research directions on biological effects and related mechanisms of allicin.

Allicin, a thiosulfonate extract from freshly minced garlic, has been reported to have various biological effects on different organs and systems of animals and human. It can reduce oxidative stress, inhibit inflammatory response, resist pathogen infection and regulate intestinal flora. In addition, dozens of studies also demonstrated allicin could reduce blood glucose level, protect cardiovascular system and nervous system, and fight against cancers. Allicin was widely used in disease prevention and health care. However, more investigations on human cohort study are needed to verify the biological or clinical effects of allicin in the future. In this review, we summarized the biological effects of allicin from previous outstanding and valuable studies and provided useful information for future studies on the health effects of allicin.

Vitamin D Status, Vitamin D Receptor Polymorphisms, and Risk of Microvascular Complications Among Individuals With Type 2 Diabetes: A Prospective Study.

OBJECTIVE: Evidence is limited regarding the associations between vitamin D status and microvascular complications in individuals with type 2 diabetes (T2D), among whom vitamin D deficiency or insufficiency is particularly common. In this study we aimed to prospectively investigate the associations of serum 25-hydroxyvitamin D [25(OH)D] and vitamin D receptor (VDR) polymorphisms with risk of diabetic microvascular complications. RESEARCH DESIGN AND METHODS: This analysis included 14,709 participants with T2D who were free of microvascular complications from the UK Biobank. Incidence of diabetic microvascular complications was ascertained via electronic health records. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: Median serum 25(OH)D concentration was 40.7 nmol/L (interquartile range 27.5, 56.4). During a median of 11.2 years of follow-up, 1,370 people developed diabetic microvascular complications. Compared with participants with 25(OH)D <25 nmol/L, individuals with 25(OH)D ≥75 nmol/L had a multivariable-adjusted HR of 0.65 (95% CI 0.51, 0.84) for composite diabetic microvascular complications, 0.62 (0.40, 0.95) for diabetic retinopathy, 0.56 (0.40, 0.79) for diabetic nephropathy, and 0.48 (0.26, 0.89) for diabetic neuropathy. In addition, in comparisons with participants with 25(OH)D <25 nmol/L and minor allele homozygotes (TT of rs1544410 and GG of rs731236), the multivariable-adjusted HRs of composite diabetic microvascular complications were 0.54 (0.38, 0.78) and 0.55 (0.38, 0.80) for participants with serum 25(OH)D ≥50 nmol/L and major allele homozygotes (CC and AA), respectively, although no significant interaction was observed. CONCLUSIONS: Higher serum 25(OH)D concentrations were significantly associated with lower risk of diabetic microvascular complications, including diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. Our findings suggest a potential beneficial role of maintaining adequate vitamin D status in the prevention of diabetic microvascular complications.

Proton Pump Inhibitor Use and Risks of Cardiovascular Disease and Mortality in Patients With Type 2 Diabetes.

CONTEXT: Proton pump inhibitors (PPIs) are widely used drugs for gastric acid-related diseases and may affect the gut microbiome. OBJECTIVE: We aimed to evaluate the associations of PPI use with risks of cardiovascular disease (CVD) and all-cause mortality in patients with type 2 diabetes (T2D). METHODS: We analyzed the associations of PPI use with risks of coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), stroke, and all-cause mortality in 19 229 adults with T2D using data from the UK Biobank study. RESULTS: During a median follow-up of 10.9 to 11.2 years, we documented 2971 CAD, 1827 MI, 1192 HF, and 738 stroke cases, along with 2297 total deaths. PPI use was significantly associated with higher risks of CAD (hazard ratio [HR], 1.27; 95% CI, 1.15-1.40), MI (HR, 1.34; 95% CI, 1.18-1.52), HF (HR, 1.35; 95% CI, 1.16-1.57), and all-cause mortality (HR, 1.30; 95% CI, 1.16-1.45). No statistically significant association was observed between PPI use and stroke (HR, 1.11; 95% CI, 0.90-1.36). The results were consistent in the subgroup analyses stratified by factors including indications of PPI, antidiabetic medication use, and antiplatelet drug use. Analyses in a 1:1 propensity score-matched cohort of PPI users vs nonusers yielded similar results. CONCLUSION: Our data suggest that PPI use is associated with higher risks of CVD events and mortality among patients with T2D. The benefits and risks of PPI use should be carefully balanced among patients with T2D, and monitoring of adverse CVD events during PPI therapy should be enhanced.

Associations of healthy dietary patterns with mortality among people with prediabetes.

PURPOSE: To examine the associations of healthy dietary patterns with cardiometabolic biomarkers and all-cause mortality among individuals with prediabetes. METHODS: This cohort study included 8363 adults with prediabetes from the National Health and Nutrition Examination Survey 1999-2014. Healthy dietary patterns including Alternate Healthy Eating Index-2010 (AHEI-2010), Alternate Mediterranean Diet score (AMED), Dietary Approaches to Stop Hypertension score (DASH), and Healthy Eating Index-2015 (HEI-2015) were calculated based on 24-h dietary recall data. Mortality status was obtained by linkage to National Death Index records. Cardiometabolic biomarkers, including blood glucose, insulin, HbA1c, C-reactive protein (CRP), and lipids, were measured at recruitment. RESULTS: During 61,991 person-years of follow-up, 991 deaths occurred. Comparing the extreme quartiles, the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause mortality were 0.65 (0.49, 0.85) for AHEI-2010 (P-trend = 0.002), 0.68 (0.50, 0.92) for AMED (P-trend = 0.004), 0.72 (0.53, 0.98) for DASH (P-trend = 0.03), and 0.78 (0.58, 1.05) for HEI-2015 (P-trend = 0.08). Besides, the HRs (95% CIs) for all-cause mortality per 20-percentile increment in scores were 0.78 (0.67, 0.90) for AHEI-2010 (P = 0.001), 0.73 (0.62, 0.86) for AMED (P < 0.001), 0.84 (0.69, 1.02) for DASH (P = 0.08), and 0.86 (0.74, 1.00) for HEI-2015 (P = 0.04). In addition, higher dietary scores were associated with favorable blood glucose, insulin, HOMA-IR, blood lipids, and CRP (all P-trend < 0.05). The high-density lipoprotein cholesterol and CRP explained 1.53-9.21% of the associations between dietary patterns and all-cause mortality (P < 0.05). CONCLUSIONS: Diets with higher AHEI-2010, AMED, DASH, and HEI-2015 were associated with improved cardiometabolic factors and lower all-cause mortality among individuals with prediabetes. These findings suggest that multiple healthy dietary patterns instead of a one-size-fits-all diet plan might be beneficial and acceptable for individuals with prediabetes.